Using Alternating Electric Fields to Increase Permeability of the Blood Brain Barrier

Abstract

Many drugs and other molecules cannot ordinarily traverse the blood brain barrier (BBB). However, when alternating electric fields at certain optimum frequencies (e.g., 100 kHz) are applied to the brain, the BBB becomes permeable to those molecules. When the alternating electric fields are discontinued, the BBB eventually recovers to its original impermeable state. Subsequently, re-application of alternating electric fields at the optimum frequencies will re-open the BBB. Ordinarily, many frequencies (e.g., 200 kHz) of alternating electric fields are either ineffective or less effective at inducing permeability than the optimum frequencies. But once the BBB has been opened by applying alternating electric fields at the optimum frequencies, alternating electric fields at non-optimum frequencies can maintain the permeability of a previously-opened BBB.

1 - 22 . (canceled) 
     
     
         23 . A method for influencing a condition of a blood brain barrier of a subject's brain, the method comprising:
 applying a first alternating electric field to the subject's brain for a first period of time, wherein the first alternating electric field has a frequency between 25 kHz and 190 kHz and wherein the first period of time is at least 24 hours;   administering a first substance to the subject after the first period of time has elapsed;   turning off the first alternating electric field after the first period of time has elapsed and leaving the first alternating electric field off for a third period of time, wherein the third period of time is at least 48 hours;   after the third period of time has elapsed, applying a second alternating electric field to the subject's brain for a second period of time, wherein the second alternating electric field has a frequency between 25 kHz and 190 kHz and wherein the second period of time is at least 24 hours; and   administering a second substance to the subject after the second period of time has elapsed.   
     
     
         24 . The method of  claim 23 , wherein the first alternating electric field has a frequency between 50 kHz and 190 kHz, and wherein the second alternating electric field has a frequency between 50 kHz and 190 KHz. 
     
     
         25 . The method of  claim 23 , wherein the first alternating electric field has a frequency between 75 kHz and 125 kHz, and wherein the second alternating electric field has a frequency between 75 kHz and 125 kHz. 
     
     
         26 . The method of  claim 23 , wherein the first period of time is at least 48 hours and wherein the second period of time is at least 48 hours. 
     
     
         27 . The method of  claim 23 , wherein the third period of time is at least 96 hours. 
     
     
         28 . The method of  claim 23 , wherein the first alternating electric field has a field strength of at least 1 V/cm in at least a portion of the subject's brain, and wherein the second alternating electric field has a field strength of at least 1 V/cm in at least a portion of the subject's brain. 
     
     
         29 . The method of  claim 23 , wherein the administering of the second substance is performed intravenously. 
     
     
         30 . The method of  claim 23 , wherein the administering of the second substance is performed orally. 
     
     
         31 . The method of  claim 23 , wherein the first substance and the second substance are identical. 
     
     
         32 . The method of  claim 23 , wherein at least one of the first substance and the second substance comprises paclitaxel. 
     
     
         33 . The method of  claim 23 , further comprising, after the third period of time has elapsed, applying a third alternating electric field having a third frequency to the subject's brain, wherein the third frequency is between 25 kHz and 190 kHz and wherein the second and third frequencies are different. 
     
     
         34 . A method for delivering a substance across a blood brain barrier of a subject's brain, the method comprising:
 applying a first alternating electric field at a first frequency to the subject's brain for a first period of time, wherein the first alternating electric field has a frequency between 25 kHz and 190 kHz, and wherein the first period of time is at least 24 hours;   turning off the first alternating electric field at the end of the first period of time;   subsequent to the first period of time, applying a second alternating electric field at a second frequency to the subject's brain for a second period of time, wherein the second frequency is different from the first frequency, and wherein the second alternating electric field has a frequency of at least 190 kHz, and wherein the second period of time is at least 24 hours; and   administering the substance to the subject at least 24 hours after the end of the first period of time.   
     
     
         35 . The method of  claim 34 , wherein the first frequency is between 50 kHz and 190 KHz. 
     
     
         36 . The method of  claim 34 , wherein the first frequency is at least 50 kHz and the second frequency is higher than the first frequency. 
     
     
         37 . The method of  claim 34 , wherein the second period of time comprises a single uninterrupted interval of time that is at least one week long. 
     
     
         38 . The method of  claim 34 , wherein the second period of time comprises a plurality of non-contiguous intervals of time during which the second alternating electric field at the second frequency is applied to the subject's brain, wherein the plurality of non-contiguous intervals of time collectively add up to at least one week. 
     
     
         39 . The method of  claim 34 , wherein the first alternating electric field has a field strength of at least 1 V/cm in at least a portion of the subject's brain, and wherein the second alternating electric field has a field strength of at least 1 V/cm in at least a portion of the subject's brain. 
     
     
         40 . The method of  claim 34 , wherein the administering of the substance is performed intravenously. 
     
     
         41 . The method of  claim 34 , wherein the administering of the substance is performed orally. 
     
     
         42 . The method of  claim 34 , further comprising, subsequent to the first period of time, applying a third alternating electric field having a third frequency to the subject's brain, wherein the third frequency is between 25 kHz and 190 kHz, and wherein the first and third frequencies are all different.